Indazole carboxamides as kinase inhibitors

ABSTRACT

Compounds having formula (I), and enantiomers, and diastereomers, stereoisomers, pharmaceutically-acceptable salts thereof, are useful as kinase modulators, including RIPK1 modulation. All the variables are as defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to priority pursuant to 35 U.S.C. § 119(e)to U.S. provisional patent application No. 62/730,611, filed Sep. 13,2018, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds that inhibit receptorinteracting protein kinases and methods of making and using the same.Specifically, the present invention relates to indazolecarboxamides asreceptor interacting protein kinase 1 (RIPK1) inhibitors.

BACKGROUND OF THE INVENTION

Apoptosis and necrosis represent two different mechanisms of cell death.Apoptosis is a highly regulated process involving the caspase family ofcysteine proteases, and characterized by cellular shrinkage, chromatincondensation, and DNA degradation. In contrast, necrosis is associatedwith cellular and organelle swelling and plasma membrane rupture withensuing release of intracellular contents and secondary inflammation(Kroemer et al., (2009) Cell Death Differ 16:3-11). Necrosis has beenconsidered a passive, unregulated form of cell death; however, recentevidence indicates that some necrosis can be induced by regulated signaltransduction pathways such as those mediated by receptor interactingprotein kinases (RIPKs) especially in conditions where caspases areinhibited or cannot be activated efficiently (Golstein P & Kroemer G(2007) Trends Biochem. Sci. 32:37-43; Festjens et al. (2006) Biochim.Biophys. Acta 1757:1371-1387). Stimulation of the Fas and TNFR family ofdeath domain receptors (DRs) is known to mediate apoptosis in most celltypes through the activation of the extrinsic caspase pathway. Inaddition, in certain cells deficient for caspase-8 or treated withpan-caspase inhibitor Z-VAD, stimulation of death domain receptors (DR)causes a receptor interacting protein kinase 1 (RIPK1) dependentprogrammed necrotic cell death instead of apoptosis (Holler et al.(2000) Nat. Immunol. 1:489-495; Degterev et al. (2008) Nat. Chem. Biol.4:313-321). This novel mechanism of cell death is termed “programmednecrosis” or “necroptosis” (Degterev et al., (2005) Nat Chem Biol1:112-119).

Necroptosis can be triggered by a number of mechanisms including of TNFreceptor activation, Toll-like receptor engagement, genotoxic stress andviral infection. Downstream of the various stimuli, the signalingpathway that results in necroptosis is dependent on RIPK1 and RIPK3kinase activity. (He et al., (2009) Cell 137:1100-1111; Cho et. al.,(2009) Cell 137:1112-1123; Zhang et al., (2009) Science 325:332-336).

Dysregulation of the necroptosis signaling pathway has been linked toinflammatory diseases such as macrophage necrosis in atheroscelerosisdevelopment, virus-induced inflammation, systemic inflammatory responsesyndrome and ethanol-induced liver injury, neurodegeneration such asdetachment of the retina, ischemia, amyotrophic lateral sclerosis (ALS),and Gaucher's disease (Trichonas et al., (2010) Proc. Natl. Acad. Sci.107, 21695-21700; Lin et al., (2013) Cell Rep. 3, 200-210; Cho et al.,(2009) Cell, 137, 1112-1123; Duprez et al., (2011) Immunity 35, 908-918;Roychowdhury et al., Hepatology 57, 1773-1783; Vandenabeele et al.,(2010) Nature 10, 700-714; Vandenabeele et al., (2010) Sci. Signalling3, 1-8; Zhang et al., (2010) Cellular & Mol. Immunology 7, 243-249;Moriwaki et al., (2013) Genes Dev. 27, 1640-1649; Ito et al., (2016)Science 353, 603-608; Vitner et al., (2014) Nature Med. 20, 204-208).

A potent, selective, small molecule inhibitor of RIPK1 activity wouldblock RIPK1-dependent pro-inflammatory signaling and thereby provide atherapeutic benefit in inflammatory diseases characterized by increasedand/or dysregulated RIPK1 kinase activity.

SUMMARY OF THE INVENTION

The present invention provides novel indazolecarboxamides includingstereoisomers, tautomers, isotopes, prodrugs, pharmaceuticallyacceptable salts, salts, or solvates thereof, which are useful asinhibitors of RIPK1.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,isotopes, prodrugs, pharmaceutically acceptable salts, salts, orsolvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of conditions associated with aberrant RIPK1 activity.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a conditionassociated with aberrant RIPK1 activity.

In another aspect, the present invention is directed to a method oftreating diseases mediated at least partially by RIPK1 includinginflammatory diseases, ischemia, neurodegeneration, and Gaucher'sdisease, which method comprises administering to a patient in need ofsuch treatment a compound of the present invention as described above.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

In one aspect, the present invention provides, inter alia, compounds ofFormula (I) or stereoisomers, tautomers, isotopes, salts,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein

-   Ring B is piperidinyl, piperazinyl, or morpholinyl;-   R¹ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ deuteroalkyl, C₁₋₃    alkoxy, C₁₋₃ haloalkoxy, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, or C₁₋₃    deuteroalkoxy;-   R^(b) is H, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃    haloalkoxy, C₁₋₃ deuteroalkyl, C₁₋₃ deuteroalkoxy, halo, NH₂, or CN;-   R^(d) is independently H, halo, or C₁₋₃ alkyl;-   L is C(O)NR^(a);-   R^(a) is independently H, C₁₋₄ alkyl, or C₁₋₄ deuteroalkyl;-   A is A′ or A′-L′,-   A′ is C₁₋₄ alkyl substituted with 0-1 OH, C₁₋₄ deuteroalkyl    substituted with 0-1 OH, C₃₋₆ cycloalkyl-C₀₋₃-alkyl-,    C₀₋₃-alkyl-C₃₋₆ cycloalkyl-, pyrrolyl-C₁₋₃-alkyl-, C₁₋₃-alkyl-pyrrol    yl-, pyrazolyl-C₁₋₃-alkyl-, or C₁₋₃-alkyl-pyrazolyl-;-   L′ is —O—;-   R² is phenyl, or a 5 to 6 membered heterocycle having 1-4    heteroatoms selected from N and O, wherein any of the phenyl or    heterocycle groups are substituted with 0-3 R^(2a);-   R^(2a) is halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₆ alkoxy, C₁₋₆    deuteroalkyl, C₁₋₆ deuteroalkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy,    C₃₋₆ cycloalkyl, C₃₋₆ halocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆    cycloalkyl-C₁₋₃ alkoxy-, C₃₋₆ cycloalkyl-C₁₋₃ deuteroalkoxy-, C₃₋₆    cycloalkyl-C₁₋₃ haloalkoxy-, C₁₋₆ alkoxy-C₁₋₃ alkyl-, C₃₋₆    cycloalkoxy-C₁₋₃ alkyl-, C₁₋₄ alkyl-SO₂—, C₃₋₆ cycloalkyl-SO₂—,    C₆₋₁₀ aryl-S—NR^(2c)R^(2d)CO—, heterocycle-, heterocycle-O—,    heterocycle-CH₂—, wherein each heterocycle is independently a 4-6    membered ring having 1-2 heteroatoms selected from N and O, and    wherein each alkyl, cycloalkyl, or heterocycle is substituted with    0-2 R^(2b);-   R^(2b), at each occurrence, is independently C₁₋₃ alkyl, halo, C═O,    or C₁₋₃ haloalkyl;-   R^(2c) and R^(2d) are independently selected from H, C₁₋₃ alkyl,    C₁₋₃ deuteroalkyl, C₃₋₆ cycloalkyl, or taken together with N to    which they are attached to form a 4-6 member heterocyclic ring,    having 0-1 additional heteroatoms selected from N, O and S, and    being substituted with 0-4 substituents chosen from deuterium or    halo; and-   n is 0, 1 or 2.

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   Ring B is

-    any of which are substituted with 0-1 R^(b); and-   R⁴ is H, or C₁₋₃ alkyl.

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   R² is phenyl, or pyridinyl, or pyrrolyl, any of which are    substituted with 0-3 R^(2a).

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   A′ is C₁₋₄ alkyl substituted with 0-1 OH, or C₁₋₄ deuteroalkyl    substituted with 0-1 OH.

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   R^(2a) is halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆    haloalkoxy or C₃₋₆ cycloalkyl-C₁₋₃ alkoxy-.

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   R^(b) is H, Cl, F, C₁₋₃ alkyl, or C₁₋₃ alkoxy;

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   A is —CH₂—, CD₂-, —CH₂CH₂—, —CH(CH₃)—, —CH(CD₃)-, —CH₂CH₂CH(CH₃)—,    —CH₂CH₂CH(OH)—, or —CH₂-cyclopropyl-.

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   A is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH(CH₃)—, —CH₂CH₂CH(OH)—,    —CH₂CH(OH)CH₂—O—, —CH₂CH₂CH₂O—, -cyclohexyl-, -pyrrolidinyl-CH₂—, or    —CH₂-cyclopropyl-.

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein

-   L is C(O)NH; and-   R² is phenyl substituted with 0-3 R^(2a).

Another embodiment provides a compound of Formula (I), or stereoisomers,tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates,or prodrugs thereof, wherein the compound is selected from the examples.

The present invention is also directed to pharmaceutical compositionsuseful in treating diseases associated with kinase modulation, includingthe modulation of receptor interacting protein kinases such as RIPK1,comprising compounds of formula (I), or pharmaceutically-acceptablesalts thereof, and pharmaceutically-acceptable carriers or diluents.

The invention further relates to methods of treating diseases associatedwith kinase modulation, including the modulation of receptor interactingprotein kinases such as RIPK1, comprising administering to a patient inneed of such treatment a therapeutically-effective amount of a compoundaccording to formula (I).

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides a method for treating proliferativediseases, allergic diseases, autoimmune diseases and inflammatorydiseases and fibrotic diseases, comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides a method for treating a disease,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I), whereinthe disease is inflammatory bowel disease, Crohn's disease or ulcerativecolitis, poriasis, systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), transplant rejection, nonalcoholicsteatohepatitis (NASH), or ischemia reperfusion.

The present invention also provides a method of treating a conditioncomprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I), whereinthe condition is selected from systemic lupus erythematosus (SLE),multiple sclerosis (MS), transplant rejection, acute myelogenousleukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'ssarcoma, multiple myeloma, solid tumors, ocular neovasculization, andinfantile haemangiomas, B cell lymphoma, systemic lupus erythematosus(SLE), psoriatic arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis,multiple sclerosis (MS), transplant rejection, Type I diabetes,membranous nephritis, autoimmune hemolytic anemia, autoimmunethyroiditis, cold and warm agglutinin diseases, Evan's syndrome,hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP),sarcoidosis, Sjogren's syndrome, peripheral neuropathies, pemphigusvulgaris and asthma, nonalcoholic steatohepatitis (NASH), or ischemiareperfusion.

The present invention also provides a method of treating a conditioncomprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I), whereinthe condition is selected from macrophage necrosis in atheroscelerosisdevelopment, virus-induced inflammation, systemic inflammatory responsesyndrome and ethanol-induced liver injury, neurodegeneration such asdetachment of the retina, retinal degeneration, wet and dry age-relatedmacular degeneration (AMD), ischemia, amyotrophic lateral sclerosis(ALS), and Gaucher's disease.

The present invention also provides a method of treating a conditioncomprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I), whereinthe condition is selected from inflammatory bowel disease, ulcerativecolitis, Crohn's disease, psoriasis, rheumatoid arthritis (RA), heartfailure, and nonalcoholic steatohepatitis (NASH).

The present invention also provides a method of treating a conditioncomprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I), whereinthe condition is selected from inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, and psoriasis.

The present invention also provides a method of treating a conditioncomprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I), whereinthe condition is selected from nonalcoholic steatohepatitis (NASH), andischemia reperfusion.

The present invention also provides a method for treating rheumatoidarthritis, comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula(I),

The present invention also provides a method of treating diseases,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula (I), orpharmaceutically acceptable salt thereof, in combination with othertherapeutic agents.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, isotopes, salts, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for use in therapy.

In another embodiment, compounds of formula (I), are selected fromexemplified examples or combinations of exemplified examples or otherembodiments herein.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, isotopes, salts,pharmaceutically acceptable salts, solvates, or prodrugs thereof, forthe manufacture of a medicament for the treatment of cancers, anallergic disease, an autoimmune disease or an inflammatory disease.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects and/orembodiments of the invention noted herein. It is understood that any andall embodiments of the present invention may be taken in conjunctionwith any other embodiment or embodiments to describe additionalembodiments. It is also to be understood that each individual element ofthe embodiments is its own independent embodiment. Furthermore, anyelement of an embodiment is meant to be combined with any and all otherelements from any embodiment to describe an additional embodiment.

The following are definitions of terms used in this specification andappended claims. The initial definition provided for a group or termherein applies to that group or term throughout the specification andclaims, individually or as part of another group, unless otherwiseindicated.

When any variable (e.g., R³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R³, then saidgroup may optionally be substituted with up to two R³ groups and R³ ateach occurrence is selected independently from the definition of R³.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these can be converted to N-oxides by treatmentwith an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, all shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

A dash that is not between two letters or symbols is used to indicate apoint of attachment for a substituent. For example, —CONH₂ is attachedthrough the carbon atom.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula (I), (e.g., an optionally substituted heteroarylgroup) refers to a moiety having 0, 1, 2, or more substituents. Forexample, “optionally substituted alkyl” encompasses both “alkyl” and“substituted alkyl” as defined below. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl”(or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can beunsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

When the term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the substituted alkyl will contain. Forexample, “arylalkyl” refers to a substituted alkyl group as definedabove where at least one of the substituents is an aryl, such as benzyl.Thus, the term aryl(C₀₋₄)alkyl includes a substituted lower alkyl havingat least one aryl substituent and also includes an aryl directly bondedto another group, i.e., aryl(C₀)alkyl. The term “heteroarylalkyl” refersto a substituted alkyl group as defined above where at least one of thesubstituents is a heteroaryl.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more doublecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more triplecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

When reference is made to a substituted alkenyl, alkynyl, alkylene,alkenylene, or alkynylene group, these groups are substituted with oneto three substituents as defined above for substituted alkyl groups.

The term “alkoxy” refers to an oxygen atom substituted by alkyl orsubstituted alkyl, as defined herein. For example, the term “alkoxy”includes the group —O—C₁₋₆alkyl such as methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, andthe like. “Lower alkoxy” refers to alkoxy groups having one to fourcarbons.

It should be understood that the selections for all groups, includingfor example, alkoxy, thioalkyl, and aminoalkyl, will be made by oneskilled in the field to provide stable compounds.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo, or keto, (i.e., ═O)then 2 hydrogens on the atom are replaced. Keto substituents are notpresent on aromatic moieties. Unless otherwise specified, substituentsare named into the core structure. For example, it is to be understoodthat when (cycloalkyl)alkyl is listed as a possible substituent, thepoint of attachment of this substituent to the core structure is in thealkyl portion. Ring double bonds, as used herein, are double bonds thatare formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture to a useful degree of purity, and subsequentformulation into an efficacious therapeutic agent. It is preferred thatthe presently recited compounds do not contain a N-halo, S(O)₂H, orS(O)H group.

The term “carbocyclyl” or “carbocyclic” refers to a saturated orunsaturated, or partially unsaturated, monocyclic or bicyclic ring inwhich all atoms of all rings are carbon. Thus, the term includescycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ringatoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or[6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6]system. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Carbocycles, can include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and phenyl. When the term “carbocycle” is used, it isintended to include “aryl”. A bridged ring occurs when one or morecarbon atoms link two non-adjacent carbon atoms. Preferred bridges areone or two carbon atoms. It is noted that a bridge always converts amonocyclic ring into a bicyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,and naphthyl groups, each of which may be substituted. A preferred arylgroup is optionally-substituted phenyl.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbomyl, and the like, which optionally may be substitutedat any available atoms of the ring(s).

The terms “heterocycloalkyl”, “heterocyclo”, “heterocycle”,“heterocyclic”, or “heterocyclyl” may be used interchangeably and referto substituted and unsubstituted aromatic or non-aromatic 3- to7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10-to 15-membered tricyclic groups, in which at least one of the rings hasat least one heteroatom (O, S or N), said heteroatom containing ringpreferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Eachring of such a group containing a heteroatom can contain one or twooxygen or sulfur atoms and/or from one to four nitrogen atoms providedthat the total number of heteroatoms in each ring is four or less, andfurther provided that the ring contains at least one carbon atom. Thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenatoms may optionally be quaternized. The fused rings completing thebicyclic and tricyclic groups may contain only carbon atoms and may besaturated, partially saturated, or unsaturated. The heterocyclo groupmay be attached at any available nitrogen or carbon atom. The term“heterocycle” includes “heteroaryl” groups. As valence allows, if saidfurther ring is cycloalkyl or heterocyclo it is additionally optionallysubstituted with ═O (oxo).

Exemplary monocyclic heterocyclyl groups include azetidinyl,pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl,morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like,including the exemplary groups listed under “heteroaryl”. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups,and 11- to 14-membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings, saidheteroatom-containing ring preferably having 1, 2, or 3 heteroatomsselected from O, S, and N. Each ring of the heteroaryl group containinga heteroatom can contain one or two oxygen or sulfur atoms and/or fromone to four nitrogen atoms provided that the total number of heteroatomsin each ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. As valence allows, if said further ring is cycloalkylor heterocyclo it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl, and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g, cyclohexyl),heterocyclo (e.g, pyrrolidinyl, piperidinyl, and morpholinyl) orheteroaryl (e.g, tetrazolyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, and furyl) the reference is intended to include rings having0 to 3, preferably 0-2, substituents, as appropriate.

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes OCF₃.

The term “deuteroalkyl” means a substituted alkyl having one or moredeuterium atom. For example, the term “deuteroalkyl” includes mono, bi,and trideuteromethyl.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

One skilled in the field will understand that, when the designation“CO₂” is used herein, this is intended to refer to the group

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The compounds of formula (I) may exist in a free form (with noionization) or can form salts which are also within the scope of thisinvention. Unless otherwise indicated, reference to an inventivecompound is understood to include reference to the free form and tosalts thereof. The term “salt(s)” denotes acidic and/or basic saltsformed with inorganic and/or organic acids and bases. In addition, theterm “salt(s) may include zwitterions (inner salts), e.g., when acompound of formula (I), contains both a basic moiety, such as an amineor a pyridine or imidazole ring, and an acidic moiety, such as acarboxylic acid. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, such as, for example,acceptable metal and amine salts in which the cation does not contributesignificantly to the toxicity or biological activity of the salt.However, other salts may be useful, e.g., in isolation or purificationsteps which may be employed during preparation, and thus, arecontemplated within the scope of the invention. Salts of the compoundsof the formula (I) may be formed, for example, by reacting a compound ofthe formula (I) with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxy ethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts; alkaline earth metal salts such ascalcium and magnesium salts; barium, zinc, and aluminum salts; saltswith organic bases (for example, organic amines) such as trialkylaminessuch as triethylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamineor similar pharmaceutically acceptable amines and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g, decyl, lauryl, myristyl and stearylchlorides, bromides and iodides), aralkyl halides (e.g, benzyl andphenethyl bromides), and others. In one embodiment, salts includemonohydrochloride, hydrogensulfate, methanesulfonate, phosphate ornitrate salts.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, the disclosure of which is hereby incorporated by reference.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.Stereoisomers may include compounds which are optical isomers throughpossession of one or more chiral atoms, as well as compounds which areoptical isomers by virtue of limited rotation about one or more bonds(atropisomers). The definition of compounds according to the inventionembraces all the possible stereoisomers and their mixtures. It veryparticularly embraces the racemic forms and the isolated optical isomershaving the specified activity. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates from the conventionalmethods, such as, for example, salt formation with an optically activeacid followed by crystallization.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. As an example, an alkyl substituent is intended to coveralkyl groups have either hydrogen, deuterium, and/or some combinationthereof. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeledcompounds of the invention can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described herein, using an appropriate isotopically-labeledreagent in place of the non-labeled reagent otherwise employed.

Prodrugs and solvates of the inventive compounds are also contemplated.The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula (I), and/or a salt and/orsolvate thereof. Any compound that will be converted in vivo to providethe bioactive agent (i.e., the compound for formula (I)) is a prodrugwithin the scope and spirit of the invention. For example, compoundscontaining a carboxy group can form physiologically hydrolyzable esterswhich serve as prodrugs by being hydrolyzed in the body to yield formula(I) compounds per se. Such prodrugs are preferably administered orallysince hydrolysis in many instances occurs principally under theinfluence of the digestive enzymes. Parenteral administration may beused where the ester per se is active, or in those instances wherehydrolysis occurs in the blood. Examples of physiologically hydrolyzableesters of compounds of formula (I) include C₁₋₆alkylbenzyl,4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 112, pp. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and    Application of Prodrugs,” by H. Bundgaard, pp. 113-191 (1991); and-   c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, pp. 1-38    (1992), each of which is incorporated herein by reference.

Compounds of the formula (I) and salts thereof may exist in theirtautomeric form, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that theall tautomeric forms, insofar as they may exist, are included within theinvention.

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated. All geometricisomers, tautomers, atropisomers, hydrates, solvates, polymorphs, andisotopically labeled forms of the compounds referred to herein, andmixtures thereof, are considered within the scope of the presentinvention. Methods of solvation are generally known in the art.

Utility

The compounds of the invention modulate kinase activity, including themodulation of RIPK1. Accordingly, compounds of formula (I) have utilityin treating conditions associated with the modulation of kinaseactivity, and particularly the selective inhibition of RIPK1 activity.In another embodiment, compounds of formula (I) have advantageousselectivity for RIPK1 activity preferably from at least 20 fold to over1,000 fold more selective over other kinases.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of RIPK1, compounds ofFormula (I) are useful in treating RIPK1-associated conditionsincluding, but not limited to, inflammatory diseases such as Crohn'sdisease and ulcerative colitis, inflammatory bowel disease, asthma,graft versus host disease, chronic obstructive pulmonary disease;autoimmune diseases such as Graves' disease, rheumatoid arthritis,systemic lupus erythematosis, psoriasis; destructive bone disorders suchas bone resorption disease, osteoarthritis, osteoporosis, multiplemyeloma-related bone disorder; proliferative disorders such as acutemyelogenous leukemia, chronic myelogenous leukemia; angiogenic disorderssuch as angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, ALS, cerebralischemias or neurodegenerative disease caused by traumatic injury,oncologic and viral diseases such as metastatic melanoma, Kaposi'ssarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS;fibrotic conditions such as, nonalcoholic steatohepatitis (NASH); andcardiac conditions such as, ischemia reperfusion; respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, ALS, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoisosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, meloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hyposia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Preferred methods of treatment are those wherein thecondition is selected from inflammatory bowel disease, Crohn's diseaseand ulcerative colitis, allograft rejection, rheumatoid arthritis,psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigusvulgaris, and nonalcoholic steatohepatitis (NASH), and ischemiareperfusion. Alternatively preferred methods of treatment are thosewherein the condition is selected from ischemia reperfusion injury,including cerebral ischemia reperfusions injury arising from stroke andcardiac ischemia reperfusion injury arising from myocardial infarction.

When the terms “RIPK1-associated condition” or “RIPK1-associated diseaseor disorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is affected by RIPK1 kinase activity.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula (I)or a salt thereof. “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibit RIPK1.

The methods of treating RIPK1 kinase-associated conditions may compriseadministering compounds of Formula (I) alone or in combination with eachother and/or other suitable therapeutic agents useful in treating suchconditions. Accordingly, “therapeutically effective amount” is alsointended to include an amount of the combination of compounds claimedthat is effective to inhibit RIPK1 and/or treat diseases associated withRIPK1.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; anti-inflammatory anti-bodies such as vedolizumab andustekinumab, anti-infammatory kinase inhibitors such as TYK2 inhibitors,antiviral agents such as abacavir; antiproliferative agents such asmethotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugssuch as azathiprine and cyclophosphamide; TNF-α inhibitors such astenidap, anti-TNF antibodies or soluble TNF receptor, rapamycin(sirolimus or Rapamune) or derivatives thereof, and agonists of FGF21.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating RIPK1kinase-associated conditions, including IL-1, IL-6, IL-8, IFNγ andTNF-α-mediated conditions, as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th ed., 1985, which is incorporated herein by reference inits entirety.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrastemal injection orinfusion techniques (e.g, as sterile injectable aq. or non-aq. solutionsor suspensions); nasally such as by inhalation spray; topically, such asin the form of a cream or ointment; rectally such as in the form ofsuppositories; or liposomally. Dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents may beadministered. The compounds may be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved with suitable pharmaceutical compositions or,particularly in the case of extended release, with devices such assubcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g, CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents andstabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The therapeutically-effective amount of a compound of the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for a mammal of from about 0.05 to1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species, that are affected by mediation of RIPK1 enzymelevels.

MLKL Phosphorylation High-Content Assay

HT29-L23 human colorectal adenocarcinoma cells were maintained in RPMI1640 medium containing 10% heat-inactivated FBS, 1%Penicillin-Streptomycin and 10 mM HEPES. Cells were seeded at 2,000cells/well in 384 well tissue culture-treated microplates (Greiner#781090-3B) and incubated at 37° C. (5% CO₂/95% O₂) for 2 d. On the dayof the assay, the cells were treated with test compounds at finalconcentrations of 6.25 to 0.106 μM for 30 min at 37° C. (5% CO₂/95% O₂).Necroptopsis was induced using a mixture of human TNFα (35 ng/mL)(Peprotech #300-01A), SMAC mimetic (from US 2015/0322111 A1) (700 nM)and Z-VAD (140 nM) (BD pharmingen #51-6936). Following 6 h incubation at37° C. (5% CO₂/95% O₂), the cells were fixed with 4% formaldehyde (ACROS11969-0010) for 15 min at rt, then permeabilized with phosphate bufferedsaline (PBS) containing 0.2% Triton-X-100 for 10 min. MLKLphosphorylation was detected using anti-MLKL (phospho S358) antibody(Abeam #ab 187091) (1:1000 dilution in Blocking Buffer [PBS supplementedwith 0.1% BSA]) with ON incubation at 4° C. After washing three times inPBS, goat anti-rabbit Alexa-488 (1:1000 dilution) (Life Technologies,A11008) and Hoechst 33342 (Life Technologies, H3570) (1:2000 dilution)in Blocking Buffer were added for 1 h at rt. Following another threecycles of washes in PBS, the microplates were sealed, and cellularimages were acquired in the Cellomics ArrayScan VTI high-content imagerequipped with an XI camera. Fluorescent images were taken using a 10×objective and the 386-23 BGRFRN_BGRFRN and 485-20 BGRFRN_BGRFRN filtersets, for nuclei and MLKL phosphorylation, respectively. The image setswere analyzed using the Compartmental Analysis Bioapplication software(Cellomics). The level of MLKL phosphorylation was quantified asMEAN_CircRingAvglntenRatio. The maximal inhibitory response was definedby the activity induced by Neels (CAS #: 852391-15-2, 6.25 μM). The IC₅₀value was defined as the concentration of compound that produces 50% ofthe maximal inhibition. The data were fitted using the 4-parameterlogistic equation to calculate the IC₅₀ and Ymax values.

RIPK1 HTRF Binding Assay

A solution was prepared containing 0.2 nM Anti GST-Tb (Cisbio,61GSTTLB), 90.6 nM probe and 1 nM His-GST-TVMV-hRIPK1(1-324) in FRETBuffer (20 mM HEPES, 10 mM MgCl2, 0.015% Brij-35, 4 mM DTT, 0.05 mg/mLBSA). Using Formulatrix Tempest, the detection antibody/enzyme/probesolution (2 mL) was dispensed into wells of a 1536 plate (Black LowBinding Polystyrene 1536 Plate (Corning, 3724)) containing 10 nL ofcompounds of interest at appropriate concentration in DMSO. The platewas incubated at rt for 1 h. FRET was measured using the EnVision platereader (Excitation: 340 nM, Emission: 520 nM/495 nM). Total signal (0%inhibition) was calculated from wells containing 10 nL DMSO only. Blanksignal (100% inhibition) calculated from wells containing 10 nL of 15 nMstaurosporine and internal controls.

Cloning and Baculovirus Expression of RIPK1 Construct

The coding region of human RIPK1(1-324) flanked by NdeI site at 5′ endand stop codon TGA and XhoI site at 3′ end was codon optimized and genesynthesized at GenScript USA Inc. (Piscataway, N.J.) and subcloned intoa modified pFastBac1 vector (Invitrogen, Carlsbad, Calif.) withN-terminal His-GST-TVMV tag, to generate His-GST-TVMV-hRIPK1(1-324)-pFB.The fidelity of the synthetic fragment was confirmed by sequencing.

Baculovirus was generated for the construct using the Bac-to-Bacbaculovirus expression system (Invitrogen) according to themanufacturer's protocol. Briefly, recombinant bacmid was isolated fromtransformed DH10Bac E. coli competent cells (Invitrogen) and used totransfect Spodoptera frugiperda (Sf9) insect cells (Invitrogen).Baculovirus was harvested 72 hours post transfection and a virus stockwas prepared by infecting fresh Sf9 cells at a 1/1000 (v/v) ratio for 66hours.

For large scale protein production, Sf9 cells (Expression System, Davis,Calif.) grown in ESF921 insect medium (Expression System) at 2×106cells/ml were infected with virus stock at a 1/100 (v/v) ratio for 66hours. The production was carried out either at a 10 L scale in a 22 Lcellbag (GE Healthcare Bioscience, Pittsburgh, Pa.) or at a 20 L scalein a 50 L cellbag using WAVE-Bioreactor System 20/50 (GE HealthcareBioscience). The infected cells were harvested by centrifugation at 2000rpm for 20 min at 4° C. in a SORVALL® RC12BP centrifuge. The cellpellets was stored at −70° C. before protein was purified.

Purification of His-GST-TVMV-hRIPK1(1-324)

RIPK1 containing cell paste was resuspended in 50 mM TrispH7.5, 150 mMNaCl, 10 mM imidazole, 5% glycerol, 5 mM MgSO₄, 1 mM TCEP, 25 U/mlBenzonase, and Complete Protease Inhibitor tablets (1/50 ml, RocheDiagnostics, Indianapolis, Ind.). The cells were lysed by nitrogencavitation using an unstirred pressure vessel @ 525 PSI (Parr InstrumentCompany, Moline, Ill.). The suspension was clarified by centrifugationat 136,000×g for 40 min, at 4° C. The lysate was decanted from thepellet and passed through a 5 ml NiNTA Superflow cartridge (Qiagen,Valencia, Calif.) using an AKTA Pure (GE Healthcare). Column was elutedwith 10 CV linear gradient into 50 mM Tris 7.5, 150 mM NaCl, 500 mMimidazole, 5% glycerol, 1 mM TCEP. Peak fractions were pooled and loadeddirectly onto 5 ml GSTrap 4B column (GE Healthcare). Column was washedwith 50 mM Tris 7.0, 150 mM NaCl, 5% glycerol, 1 mM DTT and eluted in 10CV linear gradient into 50 mM Tris 8.0, 150 mM NaCl, 20 mM reducedglutathione, 5% glycerol, 1 mM DTT. Fractions identified by SDS-PAGE ascontaining RIPK1 were pooled and concentrated using 30 kDa MWCO spinconcentrators (Amicon Ultra-15, Millipore, Billerica, Mass.) and loadedonto a HiLoad 26/600 Superdex 200 column (GE Healthcare) equilibrated in25 mM Tris 7.5, 150 mM NaCl, 2 mM TCEP, 5% glycerol. The RIPK1 proteineluted as a dimer off the SEC column.

The yield was ˜8 mg/L with a purity >95% as determined by Coomassiestain SDS-PAGE gel analysis. LCMS analysis of the protein showed thatthe protein had lost the N-terminal methionine, had one phosphorylatedsite, and was partially acetylated. Protein was aliquoted and stored at−80° C.

Using these assays, the IC₅₀ values of the following compounds weredetermined. See Table A.

TABLE A RIPK1 HTRF pMLKL Ex (IC50, nM) (IC50, μM) 1 290 0.662 >15,000 >6.2 3 1100 4.3 4 1100 3.2 5 25 0.19 6 52 4.3 7 170 2.2 8 5150.11 9 1000 3.5 10 410 3.6 11 540 2.5 12 110 0.29 13 1300 3.2 14 310 2.415 440 1.9 16 1600 3.1 17 22 0.20 18 >15,000 2.4 19 790 0.69 20 2200 2.321 310 1.2 22 100 0.44 23 280 1.6 24 51 0.11 25 1600 4.5 26 290 2.5

Methods of Preparation

Compounds of Formula (I), and intermediates used in the preparation ofcompounds of Formula (I), can be prepared using procedures shown in thefollowing examples and related procedures. The methods and conditionsused in these examples, and the actual compounds prepared in theseexamples, are not meant to be limiting, but are meant to demonstrate howthe compounds of Formula (I) can be prepared. Starting materials andreagents used in these examples, when not prepared by a proceduredescribed herein, are generally either commercially available, or arereported in the chemical literature, or may be prepared by usingprocedures described in the chemical literature.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “aq” or “aq.” for aqueous, “° C.” fordegrees Celsius, “eq” for equivalent or equivalents, “g” for gram orgrams, “mg” for milligram or milligrams, “L” for liter or liters, “mL”for milliliter or milliliters, “μL” for microliter or microliters, “N”for normal, “M” for molar, “mmol” for millimole or millimoles, “min” forminute or minutes, “h” for hour or hours, “rt” for room temperature,“ON” for overnight, “RT” for retention time, “atm” for atmosphere, “psi”for pounds per square inch, “cone.” for concentrate, “sat” or“saturated” for saturated, “CVs” for column volumes, “MW” for molecularweight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” or “LC/MS” for liquid chromatography massspectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC”for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography,“SFC” for supercritical fluid chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “MHz” for megahertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   -   Me methyl    -   Et ethyl    -   Pr propyl    -   i-Pr isopropyl    -   Bu butyl    -   i-Bu isobutyl    -   t-Bu tert-butyl    -   Ph phenyl    -   Bn benzyl    -   Boc tert-butyloxycarbonyl    -   AcOH or HO Ac acetic acid    -   Ac₂O acetic anhydride    -   Boc (tert-butoxy)carbonyl    -   BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate    -   CBz carbobenzyloxy    -   CH₂Cl₂ dichloromethane    -   CH₃CN or ACN acetonitrile    -   CDCl₃ deutero-chloroform    -   CHCl₃ chloroform    -   Cs₂CO₃ cesium carbonate    -   DCE 1,2 dichloroethane    -   DCM dichloromethane    -   DIEA/DIPEA/Hünig's Base diisopropylethylamine    -   DMAP 4-dimethylaminopyridine    -   DME 1,2-dimethoxy ethane    -   DMF dimethyl formamide    -   DMSO dimethyl sulfoxide    -   Et₃N or TEA triethylamine    -   EtOAc ethyl acetate    -   Et₂O diethyl ether    -   EtOH ethanol    -   HCl hydrochloric acid    -   Hex hexane    -   K₂CO₃ potassium carbonate    -   KOAc potassium acetate    -   K₃PO₄ potassium phosphate    -   LiOH lithium hydroxide    -   MeOH methanol    -   Mel iodomethane    -   MgSO₄ magnesium sulfate    -   NaCl sodium chloride    -   NaH sodium hydride    -   NaHCO₃ sodium bicarbonate    -   Na₂CO₃ sodium carbonate    -   NaOH sodium hydroxide    -   Na₂SO₃ sodium sulfite    -   Na₂SO₄ sodium sulfate    -   NBS N-bromosuccinimide    -   NCS N-chlorosuccinimide    -   NH₃ ammonia    -   NH₄Cl ammonium chloride    -   NH₄OH ammonium hydroxide    -   Pd/C palladium on carbon    -   PdCl₂(dppf)        [1,1′-bis(diphenylphosphino)-ferrocene]dichioropalladium(II)    -   PG protecting group    -   i-PrOH or IPA isopropanol    -   SiO₂ silica oxide    -   TBAI tetra-n-butyl ammonium iodide    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry(Maffrand, J. P. et al., Heterocycles, 16(1):35-7 (1981)). Generalsynthetic schemes for preparing compounds of the present invention aredescribed below. These schemes are illustrative and are not meant tolimit the possible techniques one skilled in the art may use to preparethe compounds disclosed herein. Different methods to prepare thecompounds of the present invention will be evident to those skilled inthe art. Additionally, the various steps in the synthesis may beperformed in an alternate sequence in order to give the desired compoundor compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Example compounds are typicallyprepared as racemic mixtures. Preparation of homochiral examples may becarried out by techniques known to one skilled in the art. For example,homochiral compounds may be prepared by separation of racemic productsby chiral phase preparative HPLC. Alternatively, the example compoundsmay be prepared by methods known to give enantiomerically enrichedproducts. These include, but are not limited to, the incorporation ofchiral auxiliary functionalities into racemic intermediates which serveto control the diastereoselectivity of transformations, providingenantio-enriched products upon cleavage of the chiral auxiliary.

Scheme 1 describes a synthetic route for compound 7. Hydrolysis andamide coupling can yield 3. Protection of the 1H-indazole group in 3with a para-methoxybenzyl group preceded a Buchwald reaction to yieldcompound 5. Deprotection under acidic conditions at elevatedtemperatures and hydrolysis provided compounds similar to 6. Compoundsexemplified by 7 can be formed by an amide coupling mediated by BOPreagent as shown in the scheme or an alternative amide coupling reagent.Use of an anhydride or carboxylic acid chloride may also effect thistransformation.

Scheme 2 illustrates access to compounds containing a 3-piperidinelinker (12, 13). Compound 3 can undergo Suzuki coupling reaction with 8to yield compounds like 9. Reduction and deprotection of 9 can yieldpiperidines similar to 11. The analogs exemplified by compound 12 can beaccessed via a single pot coupling reaction with diphosgene, followed bythe addition of amines. Compounds exemplified by 13 can be formed by anamide coupling mediated by BOP reagent as shown in the scheme or analternative amide coupling reagent. Use of an anhydride or carboxylicacid chloride may also effect this transformation.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography on an ISCO system was carried out using prepacked SiO₂cartridges eluting with either gradients of hexanes and ethyl acetate ordichloromethane and methanol unless otherwise indicated. Reverse phasepreparative HPLC or LCMS was carried out using C18 columns eluting withgradients of Solvent A (90% water, 10% methanol, 0.1% TFA) and Solvent B(10% water, 90% methanol, 0.1% TFA, UV 220 nm), or with gradients ofSolvent A (95% water, 5% acetonitrile, 0.1% TFA) and Solvent B (5%water, 95% acetonitrile, 0.1% TFA, UV 220 nm), or with gradients ofSolvent A (98% water, 2% acetonitrile, 0.05% TFA) and Solvent B (98%acetonitrile, 2% water, 0.05% TFA, UV 254 nm), or with gradients ofSolvent A (95% water, 5% acetonitrile with 10 mM ammonium acetate) andSolvent B (95% acetonitrile, 5% water with 10 mM ammonium acetate).

In the majority of examples, two analytical LCMS injections were used todetermine final purity.

Method A: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μMparticles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75 minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobilephase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50° C.;Gradient: 0-100% B over 3 min, then a 0.75 min hold at 100% B; Flow:1.11 mL/min; Detection: UV at 220 nm.

In a minority of examples analytical HPLC injections were used todetermine final purity.

Method A: Column: Sunfire C18, 3.0×150 mm, 3.5 μM particles; Mobilephase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5acetonitrile:water with 0.1% TFA; Gradient: 0-100% B over 10 minutes;Flow: 1 mL/min; Detection: UV at 220 and 254 nm

Method B: Column: Xbridge Phenyl, 3.0×150 mm, 3.5 μM particles; Mobilephase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5acetonitrile:water with 0.1% TFA; Gradient: 0-100% B over 10 minutes;Flow: 1 mL/min; Detection: UV at 220 and 254 nm

Method C: Column: XBridge C18, 3.0×150 mm, 3.5 μM particles; Mobilephase A: 5:95 methanol:water with 10 mM ammonium bicarbonate; Mobilephase B: 95:5 methanol:water with 10 mM ammonium bicarbonate; Gradient:0-100% B over 15 minutes; Flow: 1 mL/min; Detection: UV at 220 and 254nm.

Method D: Column: XBridge Phenyl, 3.0×150 mm, 3.5 μM particles; Mobilephase A: 5:95 methanol:water with 10 mM ammonium bicarbonate; Mobilephase B: 95:5 methanol:water with 10 mM ammonium bicarbonate; Gradient:0-100% B over 15 minutes; Flow: 1 mL/min; Detection: UV at 220 and 254nm.

A majority of mass spectra runs were: LCMS (ESI) m/z: [M+H]⁺ BEH C18,2.11×50 mm, 1.7 μm; Mobile phase A: 2:98 water:acetonitrile with 0.1%TFA; Mobile phase B: 98:2 acetonitrile:water with 0.1% TFA; Gradient:0-100% B over 2 minutes; Flow: 0.8 mL/min; Detection: UV at 220 nm.

NMR spectra were run with water suppression, unless otherwise noted.When water suppression affected characterization of the compounds byNMR, it is noted in the text.

Example 1N-methyl-6-[3-({[2-(trifluoromethoxy)phenyl]methyl}carbamoyl)piperidin-1-yl]-1H-indazole-3-carboxamide

1A: 6-bromo-1H-indazole-3-carboxylic acid: A solution of methyl6-bromo-1H-indazole-3-carboxylate (5 g, 19.60 mmol) and 1 N NaOH (49.0mL, 49.0 mmol) in MeOH (70 mL) was heated to 80° C. for 2 h. Thereaction mixture was concentrated to yield a crude product which wasdissolved in water (100 mL). The aqueous solution was acidified at 0° C.with 1 N HCl solution until the pH reached about 4-5. The solid wascollected as 6-bromo-1H-indazole-3-carboxylic acid (4.60 g, 19.08 mmol,97%).

MS ESI m/z 241.1 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 8.08 (dd, J=8.7, 0.6 Hz, 1H), 7.87-7.77 (m,1H), 7.41 (dd, J=8.7, 1.6 Hz, 1H).

1B: 6-bromo-N-methyl-1H-indazole-3-carboxamide: To a solution of6-bromo-1H-indazole-3-carboxylic acid (1.7 g, 7.05 mmol), methanamine,HCl (0.595 g, 8.82 mmol) and DIPEA (3.08 mL, 17.63 mmol) in DMF (25 mL)was added BOP (3.90 g, 8.82 mmol). The reaction mixture was stirred at23° C. for 16 h. The reaction mixture was concentrated. Water (100 mL)was added to the crude material and the mixture was sonicated for 10min. The solid was collected as6-bromo-N-methyl-1H-indazole-3-carboxamide (1.95 g, 7.55 mmol, 107%).

MS ESI m/z 254.0 (M+H).

1C: 6-bromo-1-(4-methoxybenzyl)-N-methyl-1H-indazole-3-carboxamide: To asolution of 6-bromo-N-methyl-1H-indazole-3-carboxamide (1.95 g, 7.67mmol) and K₂CO₃ (2.65 g, 19.19 mmol) in DMF (25 mL) was added4-methoxybenzyl chloride (1.359 mL, 9.98 mmol). The reaction mixture washeated to 70° C. for 1 h. After cooling to rt, the reaction mixture wasconcentrated and purified on a silica gel column with CH₂Cl₂/EtOAc(10/1) to yield6-bromo-1-(4-methoxybenzyl)-N-methyl-1H-indazole-3-carboxamide (2.609 g,6.72 mmol, 88%).

MS ESI m/z 374.0 (M+H).

1D: methyl1-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylate:A degassed solution of6-bromo-1-(4-methoxybenzyl)-N-methyl-1H-indazole-3-carboxamide (700 mg,1.870 mmol), methyl piperidine-3-carboxylate, HCl (504 mg, 2.81 mmol),Pd(OAc)₂ (25.2 mg, 0.112 mmol), Cs₂CO₃ (1524 mg, 4.68 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl, XPhos (89 mg,0.187 mmol) in DMF (8 mL) was heated to 100° C. for 16 h. The reactionmixture was diluted with EtOAc (150 mL). The solution was washed with10% LiCl solution (30 mL×2) and brine (30 mL) and dried over Na₂SO₄.Filtration and concentration yielded a crude product which was purifiedon a silica gel column with CH₂Cl₂/EtOAc (1/0-5/1) to yield methyl1-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylate(235 mg, 0.535 mmol, 29%).

MS ESI m/z 437.2 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=9.0 Hz, 1H), 7.19 (d, J=8.8 Hz,2H), 7.05 (dd, 0.7=9.0, 2.1 Hz, 1H), 6.89-6.83 (m, 2H), 6.80 (d, 0.7=1.8Hz, 1H), 5.52 (s, 2H), 3.74 (s, 3H), 3.72-3.62 (m, 4H), 3.53-3.43 (m,1H), 3.12 (dd, 0.7=12.5, 9.3 Hz, 1H), 2.94 (s, 3H), 2.93-2.84 (m, 1H),2.75-2.64 (m, 1H), 2.01-1.94 (m, 1H), 1.86-1.63 (m, 3H).

1E: methyl1-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylate, TFA: Asolution of methyl1-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylate(242 mg, 0.554 mmol) in TFA (0.043 mL, 0.554 mmol) was heated to 130° C.for 45 min under microwave. The reaction mixture was concentrated toyield methyl1-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylate, TFAwhich was immediately used in subsequent chemistry.

MS ESI m/z 317.2 (M+H).

1F: 1-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylic acid:A solution of methyl1-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylate (175 mg,0.554 mmol) and 1 N NaOH (1.385 mL, 1.385 mmol) in MeOH (10 mL) washeated to 100° C. for 30 min under microwave. The reaction mixture wasconcentrated to yield a crude product. Water (10 mL) was added to thecrude product and the solution acidified with IN HCl until the pH wasabout 4 to 5. The solid was collected as (205.4 mg, 0.586 mmol, 106%).

MS ESI m/z 303.2 (M+H).

1: Reagents were received in stubby tubes and placed in a BohdanMiniblock XT. A solution was prepared by dissolving1-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylic acid (150mg) in DMF (3.0 mL). Another solution was prepared by dissolving BOP(439 mg)) in DMF (3.0 mL). To a vial containing(2-(trifluoromethoxy)phenyl)methanamine (12.7 mg, 0.066 mmol) was added1-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-3-carboxylic acid (10mg, 0.033 mmol, 200 μL of the solution) followed by BOP (29.3 mg, 0.066mmol, 200 μL of the solution) and DIEA (0.029 mL, 0.165 mmol). Thereaction mixture was stirred at rt ON. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-60% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation.N-methyl-6-[3-({[2-(trifluoromethoxy)phenyl]methyl}carbamoyl)piperidin-1-yl]-1H-indazole-3-carboxamide(10.3 mg, 21.7 μmol, 65.6%) was isolated.

MS ESI m/z 476.3 (M+H)

¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (br t, J=5.6 Hz, 1H), 8.18 (br d, J=4.6Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.44-7.30 (m, 4H), 7.04 (br d, J=8.9Hz, 1H), 6.80 (s, 1H), 4.44-4.27 (m, 2H), 3.82-3.64 (m, 2H), 2.86 (br t,J=11.6 Hz, 1H), 2.79 (d, J=4.6 Hz, 3H), 2.76-2.68 (m, 1H), 2.59 (br s,1H), 1.91 (br d, J=3.4 Hz, 1H), 1.77 (br s, 1H), 1.66-1.54 (m, 2H), NHlost in water suppression.

Example 26-(3-{[(2-methoxyphenyl)methyl]carbamoyl}-4-methylpiperazin-1-yl)-N-methyl-1H-indazole-3-carboxamide

2A: 1-tert-butyl 2-methyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-1,2-dicarboxylate:A degassed solution of6-bromo-1-(4-methoxybenzyl)-N-methyl-1H-indazole-3-carboxamide (148 mg,0.395 mmol), 1-N-Boc-piperazine-2-carboxylic acid methyl ester (145 mg,0.593 mmol), Pd(OAc)₂ (5.33 mg, 0.024 mmol), Cs₂CO₃ (193 mg, 0.593 mmol)and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl, XPhos(18.85 mg, 0.040 mmol) in toluene (1 mL) was heated to 100° C. for 2 d.The reaction mixture was concentrated. Water was added and the slurrywas sonicated for 10 min. The solid was collected as 1-tert-butyl2-methyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-1,2-dicarboxylate.

MS ESI m/z 538.4 (M+H).

2B:1-(tert-butoxycarbonyl)-4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid: A solution of 1-tert-butyl 2-methyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-1,2-dicarboxylate(225 mg, 0.419 mmol) and 1 N NaOH solution (0.628 mL, 0.628 mmol) inMeOH (2 mL) was heated to 100° C. for 40 min under microwave. Thereaction mixture was concentrated. Water (10 mL) was added to the cruderesidue which was acidified until the pH was about 4. The solid wascollected as (186 mg, 0.334 mmol, 80%).

MS ESI m/z 524.4 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=9.0 Hz, 1H), 7.21 (d, J=8.8 Hz,2H), 6.90-6.84 (m, 4H), 5.54 (s, 2H), 4.78-4.65 (m, 1H), 4.32-4.20 (m,1H), 4.00-3.91 (m, 1H), 3.77-3.74 (m, 4H), 3.59 (br dd, J=7.2, 4.5 Hz,1H), 2.98-2.92 (m, 4H), 2.84-2.70 (m, 1H), 1.49 (br d, J=11.9 Hz, 9H).

2C:4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid, TFA: A solution of1-(tert-butoxycarbonyl)-4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid (144.2 mg, 0.275 mmol) and TFA (0.424 mL, 5.51 mmol) in CH₂Cl₂ (2mL) was stirred at 23° C. for 1 h. The reaction mixture was concentratedto yield4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid, TFA (163 mg, 0.274 mmol, 100%).

MS ESI m/z 424.2 (M+H).

2D:4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)-1-methylpiperazine-2-carboxylicacid: A solution of4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid, TFA (163 mg, 0.303 mmol) and formaldehyde (0.113 mL, 1.516 mmol)in CH₂Cl₂ (2 mL) and acetic acid (0.050 mL) was stirred at 23° C. for 1h. Sodium triacetoxyborohydride (64.3 mg, 0.303 mmol) was added and themixture was stirred for 16 h. The reaction mixture was concentrated andpurified on prep HPLC to yield (88 mg, 0.201 mmol, 66%).

MS ESI m/z 438.1 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=8.9 Hz, 1H), 7.20 (d, J=8.7 Hz,2H), 7.14-7.08 (m, 1H), 7.00-6.96 (m, 1H), 6.89-6.82 (m, 2H), 5.57 (s,2H), 4.14-4.00 (m, 1H), 3.87-3.77 (m, 1H), 3.75 (s, 3H), 3.70-3.61 (m,1H), 3.44-3.33 (m, 2H), 3.27-3.16 (m, 2H), 3.05 (s, 2H), 2.95 (s, 3H).

2E:1-methyl-4-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid, TFA: A solution of4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)-1-methylpiperazine-2-carboxylicacid (88 mg, 0.201 mmol) in TFA (0.015 mL, 0.201 mmol) and water (0.030mL) was heated to 120° C. for 25 min under microwave. The reactionmixture was concentrated to yieldl-methyl-4-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid, TFA (113.6 mg) which was used as is in subsequent chemistry.

MS ESI m/z 318.1 (M+H).

2: To a solution of1-methyl-4-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylicacid (15 mg, 0.047 mmol), (2-methoxyphenyl)methanamine (6.11 μl, 0.047mmol) and DIPEA (0.041 mL, 0.236 mmol) in DMF (1 mL) was added BOP (31.4mg, 0.071 mmol). The reaction mixture was stirred at 23° C. for 2 d. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-50% Bover 23 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation.6-(3-{[(2-methoxyphenyl)methyl]carbamoyl}-4-methylpiperazin-1-yl)-N-methyl-1H-indazole-3-carboxamide(3 mg, 6.9 μmol, 14.6%) was isolated.

MS ESI m/z 437.2 (M+H)

¹H NMR (500 MHz, DMSO-d₆) δ 8.30-8.20 (m, 2H), 7.94 (d, J=8.9 Hz, 1H),7.23 (br t, J=7.5 Hz, 1H), 7.16 (br d, J=7.3 Hz, 1H), 7.03 (br d, J=8.8Hz, 1H), 6.97 (br d, J=8.2 Hz, 1H), 6.89 (br t, J=7.4 Hz, 1H), 6.81 (s,1H), 4.28 (br d, J=5.7 Hz, 2H), 3.78 (s, 3H), 3.68-3.57 (m, 1H),3.03-2.73 (m, 8H), 2.35-2.26 (m, 1H), 2.19 (s, 3H).

Example 36-(2-{[3-(3,4-difluorophenyl)-3-hydroxypropyl]carbamoyl}morpholin-4-yl)-N-methyl-1H-indazole-3-carboxamide

3A: ethyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylate:A degassed solution of6-bromo-1-(4-methoxybenzyl)-N-methyl-1H-indazole-3-carboxamide (195.6mg, 0.523 mmol), ethyl morpholine-2-carboxylate (125 mg, 0.784 mmol),Pd(OAc)₂ (7.04 mg, 0.031 mmol), Cs₂CO₃ (255 mg, 0.784 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl, XPhos (24.92mg, 0.052 mmol) in toluene (3 mL) was heated to 100° C. for 16 h. Thereaction mixture was filtered and concentrated to yield a crude productwhich was purified on a silica gel column with CH₂Cl₂/EtOAc (2/1) toyield ethyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylate(99 mg, 0.208 mmol, 40%).

MS ESI m.z 453.1 (M+H)

¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=8.9 Hz, 1H), 7.16-7.10 (m, 2H),7.03 (dd, J=9.0, 2.0 Hz, 1H), 6.89-6.83 (m, 2H), 6.61 (d, J=1.7 Hz, 1H),5.46 (s, 2H), 4.36 (dd, J=9.0, 3.1 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 4.18(dt, J=11.5, 3.4 Hz, 1H), 3.90-3.81 (m, 1H), 3.78 (s, 3H), 3.70 (dd,J=12.5, 2.1 Hz, 1H), 3.38-3.31 (m, 1H), 3.12 (dd, J=12.1, 8.9 Hz, 1H),3.07-2.99 (m, 4H), 1.35 (t, J=7.2 Hz, 3H).

3B: ethyl4-(3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylate, TFA: Asolution of ethyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylate(100 mg, 0.221 mmol) in TFA (1 mL) was heated to 130° C. for 45 minunder microwave. The reaction mixture was concentrated to yield ethyl4-(3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylate, TFAwhich was used as is in subsequent chemistry.

MS ESI m/z 333.1 (M+H).

3C: 4-(3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylic acid:A solution of ethyl4-(3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylate (73.5mg, 0.221 mmol) and 1 N NaOH solution (0.553 mL, 0.553 mmol) in ethanol(2 mL) was stirred at 23° C. for 2 h. The reaction mixture wasconcentrated to yield a crude product. Water (5 mL) was added and thesolution acidified with 1 N HCl solution until the pH was about 4. Thesolid was collected as4-(3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylic acid(63.5 mg, 0.199 mmol, 90%).

MS ESI m/z 305.1 (M+H).

3: To a solution of4-(3-(methylcarbamoyl)-1H-indazol-6-yl)morpholine-2-carboxylic acid (9mg, 0.030 mmol), 3-amino-1-(3,4-difluorophenyl)propan-1-ol (5.54 mg,0.030 mmol) and DIPEA (0.013 mL, 0.074 mmol) in DMF (1 mL) was added BOP(15.70 mg, 0.035 mmol). The reaction mixture was stirred at 23° C. for 1h. The crude material was purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 10-60% B over 18 minutes, then a 3-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation.6-(2-{[3-(3,4-difluorophenyl)-3-hydroxypropyl]carbamoyl}morpholin-4-yl)-N-methyl-1H-indazole-3-carboxamide(8.6 mg, 18.2 μmol, 60.5%) was isolated.

MS ESI m/z 473.9 (M+H)

¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (br d, J=4.5 Hz, 1H), 7.99-7.89 (m,2H), 7.38-7.28 (m, 2H), 7.15 (br s, 1H), 7.05 (br d, J=8.8 Hz, 1H), 6.84(s, 1H), 4.58 (br s, 1H), 4.13-3.96 (m, 2H), 3.52 (br d, J=11.7 Hz, 1H),3.24-3.10 (m, 2H), 2.86-2.74 (m, 4H), 2.67 (br t, J=11.3 Hz, 1H),1.84-1.67 (m, 2H). 2 CHs buried by water suppression.

Example 4N-methyl-6-{3-[(3-phenylbutyl)carbamoyl]piperazin-1-yl}-1H-indazole-3-carboxamide

4A: tert-butyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)-2-((3-phenylbutyl)carbamoyl)piperazine-1-carboxylate:To a solution of1-(tert-butoxycarbonyl)-4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)piperazine-2-carboxylic acid (25 mg, 0.048mmol), 3-phenylbutan-1-amine, HCl (8.87 mg, 0.048 mmol) and DIPEA (0.021mL, 0.119 mmol) in DMF (1 mL) was added BOP (25.3 mg, 0.057 mmol). Thereaction mixture was stirred at 23° C. for 1 h. The reaction mixture wasconcentrated, water (2 mL) was added and the slurry sonicated for 5 min.The solid was collected as tert-butyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)-2-((3-phenylbutyl)carbamoyl)piperazine-1-carboxylate(58.2 mg) which was used as is in subsequent chemistry.

MS ESI m/z 655.4 (M+H)

4: A solution of tert-butyl4-(1-(4-methoxybenzyl)-3-(methylcarbamoyl)-1H-indazol-6-yl)-2-((3-phenylbutyl)carbamoyl)piperazine-1-carboxylate(58.2 mg, 0.089 mmol) in TFA (1 mL) was stirred at 23° C. for 30 min.Water (0.030 mL) was added and the reaction mixture was heated to 100°C. in an oil bath for 4 h and under microwave at 120° C. for 30 min. Thereaction mixture was concentrated and dissolved in MeOH (1 mL). Thecrude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% Bover 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation.N-methyl-6-{3-[(3-phenylbutyl)carbamoyl]piperazin-1-yl}-1H-indazole-3-carboxamide(15.6 mg, 35.9 μmol, 40.3%) was isolated.

MS ESI m/z 435 (M+H)

¹H NMR (500 MHz, DMSO-d₆) δ 8.21 (br d, J=4.7 Hz, 1H), 7.93 (br d, J=9.1Hz, 1H), 7.84 (br s, 1H), 7.28 (br d, J=4.2 Hz, 2H), 7.21 (br d, J=1.2Hz, 2H), 7.19-7.13 (m, 1H), 7.03 (br d, J=8.6 Hz, 1H), 6.77 (s, 1H),3.51 (br d, J=9.2 Hz, 1H), 3.11-2.67 (m, 11H), 1.78-1.64 (m, 2H), 1.19(br d, J=6.8 Hz, 3H). Note: One CH obscured by NMR solvent.

Example 5N-methyl-6-{1-[(3-phenylbutyl)carbamoyl]piperidin-3-yl}-1H-indazole-3-carboxamide

5A: tert-butyl3-(3-(methylcarbamoyl)-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate:A degassed solution of 6-bromo-N-methyl-1H-indazole-3-carboxamide (100mg, 0.394 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2h)-carboxylate(122 mg, 0.394 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (19.28 mg, 0.024 mmol)and potassium phosphate tribasic 2 M solution (0.590 mL, 1.181 mmol) inDMF (2.0 mL) was stirred at 100° C. for 4 h. The reaction mixture wasdiluted with EtOAc (50 mL) which was washed with 10% LiCl (20 mL×2),brine (20 mL) and dried over Na₂SO₄. Filtration and concentrationyielded a crude product which was triturated in MeOH (2 mL). The solidwas collected as tert-butyl3-(3-(methylcarbamoyl)-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(96.5 mg, 0.267 mmol, 68%).

MS ESI m/z 357.3 (M+H).

5B: tert-butyl3-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-1-carboxylate: Asuspension solution of tert-butyl3-(3-(methylcarbamoyl)-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(86.5 mg, 0.243 mmol) and Pd/C (15.50 mg, 0.015 mmol) in MeOH (5 mL) wasstirred under a H₂ balloon (0.489 mg, 0.243 mmol) for 24 h. The reactionmixture was filtered and concentrated to yield (64 mg, 0.179 mmol, 74%).

MS ESI m/z 357.4 (M−H).

5C: N-methyl-6-(piperidin-3-yl)-1H-indazole-3-carboxamide, HCl: Asolution of tert-butyl3-(3-(methylcarbamoyl)-1H-indazol-6-yl)piperidine-1-carboxylate (64 mg,0.179 mmol) and TFA (0.014 mL, 0.179 mmol) in CH₂Cl₂ (1 mL) was stirredat 23° C. for 1 h. The reaction mixture was concentrated to yield acrude material. The crude product was purified using a reverse phaseIsco chromatography (Combiflash RF200, 30 g C18 Redisep Rf highperformance gold column, solvent A: 0.1% TFA in water/MeOH (90/10),solvent B: 0.1% TFA in water/MeOH (10/90), flow rate: 35 mL/min, 10-70%B) to yield the product. The product was treated with 2.5 M HCl in EtOH(0.5 mL) and concentrated to provideN-methyl-6-(piperidin-3-yl)-1H-indazole-3-carboxamide, HCl (37 mg, 0.126mmol, 70%).

MS ESI m/z 259.1 (M+H).

5: To a solution ofN-methyl-6-(piperidin-3-yl)-1H-indazole-3-carboxamide, 6 TFA (14.6 mg,0.015 mmol) and Et₃N (10.80 μl, 0.077 mmol) in CH₂Cl₂ (1 mL) at 23° C.was added diphosgene (2.80 μl, 0.023 mmol). The reaction mixture wasstirred for 30 min. To the reaction mixture was added3-phenylbutan-1-amine (11.56 mg, 0.077 mmol) and stirring was continuedfor 48 h. The crude material was purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 20-60% B over 22 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation.N-methyl-6-{l-[(3-phenylbutyl)carbamoyl]piperidin-3-yl}-1H-indazole-3-carboxamide(4.8 mg, 11.1 μmol, 73.8%) was isolated.

MS ESI m/z 434.1 (M+H)

¹H NMR (500 MHz, DMSO-d₆) δ 8.31 (br d, J=4.6 Hz, 1H), 8.07 (d, J=8.3Hz, 1H), 7.41 (s, 1H), 7.31-7.25 (m, 2H), 7.24-7.13 (m, 4H), 6.44 (br s,1H), 4.08-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.91-2.84 (m, 1H), 2.80 (d,J=4.7 Hz, 3H), 2.77-2.62 (m, 4H), 1.93 (br d, J=9.7 Hz, 1H), 1.75-1.64(m, 4H), 1.50-1.40 (m, 1H), 1.18 (d, J=6.9 Hz, 3H).

TABLE 1 The compounds in Table 1 were prepared by methods similar tothose described in Example 1. All compounds are racemic unless otherwisenoted.

Obs Ion Ex Name R (M + H) 6 6-{3-[(2-hydroxy-3-phenoxypropyl)carbamoyl]piperidin-1-yl}-N-methyl-1H-indazole-3-carboxamide, homochiral, unknown isomer

452.2 7 6-{3-[(2-hydroxy-3- phenoxypropyl)carbamoyl]piperidin-1-yl}-N-methyl-1H-indazole-3-carboxamide, homochiral, unknown isomer

452.3 8 N-methyl-6-(3-{[(2- phenoxyphenyl)methyl]carbamoyl}piperidin-1-yl)-1H-indazole-3-carboxamide

484.0 9 6-(3-{[3- (cyclohexyloxy)propyl]carbamoyl}piperidin-1-yl)-N-methyl-1H-indazole-3-carboxamide

442.2 10 6-{3-[(3-hydroxy-3- phenylpropyl)carbamoyl]piperidin-1-yl}-N-methyl-1H-indazole-3-carboxamide, diastereomeric mixture

436.3 11 6-{3-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]piperidin-1-yl}-N-methyl-1H- indazole-3-carboxamide

457.9 12 6-[3-({[2- (cyclopropylmethoxy)phenyl]methyl}carbamoyl)piperidin-1-yl]-N-methyl-1H-indazole-3- carboxamide

462.3 13 6-(3-{[3-(4- fluorophenoxy)propyl]carbamoyl}piperidin-1-yl)-N-methyl-1H-indazole-3-carboxamide

453.9 14 6-(3-{[3-(3,4-difluorophenyl)-3-hydroxypropyl]carbamoyl}piperidin-1-yl)-N-methyl-1H-indazole-3-carboxamide, diastereomeric mixture

472.0 15 N-methyl-6-{3-[(3- phenylcyclohexyl)carbamoyl]piperidin-1-yl}-1H-indazole-3-carboxamide, diastereomeric mixture, unknown cis or trans

460.4 16 N-methyl-6-{3-[(3- phenylcyclohexyl)carbamoyl]piperidin-1-yl}-1H-indazole-3-carboxamide diastereomeric mixture, unknown cis or trans

460.4 17 N-methyl-6-{3-[(3- phenylbutyl)carbamoyl]piperidin-1-yl}-1H-indazole-3-carboxamide, diastereomeric mixture

434.4

TABLE 2 The compounds in Table 1 were prepared by methods similar tothose described in Example 2. All compounds are diastereomeric mixtures.

Obs Ion Ex Name R (M + H) 18 66-{3-[(3-hydroxy-3-phenylpropyl)carbamoyl]-4-methylpiperazin-1-yl}-N-methyl-1H-indazole- 3-carboxamide

451.3 19 6-(3-{[3-(4-fluorophenyl)butyl]carbamoyl}-4-methylpiperazin-1-yl)-N-methyl-1H-indazole-3- carboxamide

467.1 20 N-methyl-6-{4-methyl-3-[(3-phenylbutyl)carbamoyl]piperazin-1-yl}-1H- indazole-3-carboxamide

449.3

TABLE 3 The compounds in Table 1 were prepared by methods similar tothose described in Example 3. All compounds are racemic unless otherwisenoted.

Obs Ion Ex Name R (M + H) 216-{2-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]morpholin-4-yl}-N-methyl-1H-indazole-3-carboxamide

460.2 22 N-methyl-6-{2-[(3-phenylbutyl)carbamoyl]morpholin-4-yl}-1H-indazole-3-carboxamide, diastereomeric mixture

436.2 23 6-[2-({[2-(3-fluorophenyl)cyclopropyl]methyl}carbamoyl)morpholin-4-yl]-N-methyl-1H-indazole-3-carboxamide, TFA, diastereomeric mixture

452.1 24 6-(2-{[3-(4-fluorophenyl)butyl]carbamoyl}morpholin-4-yl)-N-methyl-1H-indazole-3-carboxamide, diastereomeric mixture

454.2 25 6-(2-{[3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}morpholin-4-yl)-N-methyl-1H-indazole-3-carboxamide, diastereomeric mixture

472.0 26 N-methyl-6-{2-[(3-phenylcyclohexyl)carbamoyl]morpholin-4-yl}-1H- indazole-3-carboxamide,diastereomeric mixture

462.1

1. Compounds having formula (I), or salt thereof, wherein

Ring B is piperidinyl, piperazinyl, or morpholinyl; R¹ is H, halo, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃ deuteroalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, or C₁₋₃ deuteroalkoxy; R^(b) is H, C₁₋₃alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₃ deuteroalkyl,C₁₋₃ deuteroalkoxy, halo, NH₂, or CN; R^(d) is independently H, halo, orC₁₋₃ alkyl; L is C(O)NR^(a); R^(a) is independently H, C₁₋₄ alkyl, orC₁₋₄ deuteroalkyl; A is A′ or A′-L′, A′ is C₁₋₄ alkyl substituted with0-1 OH, C₁₋₄ deuteroalkyl substituted with 0-1 OH, C₃₋₆cycloalkyl-C₀₋₃-alkyl-, C₀₋₃-alkyl-C₃₋₆ cycloalkyl-,pyrrolyl-C₁₋₃-alkyl-, C₁₋₃-alkyl-pyrrolyl-, pyrazolyl-C₁₋₃-alkyl-, orC₁₋₃-alkyl-pyrazolyl-; L′ is —O—; R² is phenyl, or a 5 to 6 memberedheterocycle having 1-4 heteroatoms selected from N and O, wherein any ofthe phenyl or heterocycle groups are substituted with 0-3 R^(2a); R^(2a)is halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₆ alkoxy, C₁₋₆deuteroalkyl, C₁₋₆ deuteroalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆cycloalkyl, C₃₋₆ halocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkyl-C₁₋₃alkoxy-, C₃₋₆ cycloalkyl-C₁₋₃ deuteroalkoxy-, C₃₋₆ cycloalkyl-C₁₋₃haloalkoxy-, C₁₋₆ alkoxy-C₁₋₃ alkyl-, C₃₋₆ cycloalkoxy-C₁₋₃ alkyl-, C₁₋₄alkyl-SO₂—, C₃₋₆ cycloalkyl-SO₂—, C₆₋₁₀ aryl-S—, NR^(2c)R^(2d)CO—,heterocycle-, heterocycle-O—, heterocycle-CH₂—, wherein each heterocycleis independently a 4-6 membered ring having 1-2 heteroatoms selectedfrom N and O, and wherein each alkyl, cycloalkyl, or heterocycle issubstituted with 0-2 R^(2b); R^(2b), at each occurrence, isindependently C₁₋₃ alkyl, halo, C═O, or C₁₋₃ haloalkyl; R^(2c) andR^(2d) are independently selected from H, C₁₋₃ alkyl, C₁₋₃ deuteroalkyl,C₃₋₆ cycloalkyl, or taken together with N to which they are attached toform a 4-6 member heterocyclic ring, having 0-1 additional heteroatomsselected from N, O and S, and being substituted with 0-4 substituentschosen from deuterium or halo; and n is 0, 1 or
 2. 2. A compound ofclaim 1, or salt thereof, wherein Ring B is

 any of which are substituted with 0-1 R^(b); and R⁴ is H, or C₁₋₃alkyl.
 3. A compound of claim 2, or salt thereof, wherein R² is phenyl,pyridinyl, or pyrrolyl, any of which are substituted with 0-3 R^(2a). 4.A compound of claim 3, or salt thereof, wherein A′ is C₁₋₄ alkylsubstituted with 0-1 OH, or C₁₋₄ deuteroalkyl substituted with 0-1 OH.5. A compound of claim 4, or salt thereof, wherein R^(2a) is halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy or C₃₋₆cycloalkyl-C₁₋₃ alkoxy-.
 6. A compound of claim 5, or salt thereof,wherein R^(b) is H, Cl, F, C₁₋₃ alkyl, or C₁₋₃ alkoxy;
 7. A compound ofclaim 6, or salt thereof, wherein A is —CH₂—, CD₂-, —CH₂CH₂—, —CH(CH₃)—,—CH(CD₃)-, —CH₂CH₂CH(CH₃)—, —CH₂CH₂CH(OH)—, or —CH₂-cyclopropyl-.
 8. Acompound of claim 6, or salt thereof, wherein A is —CH₂—, —CH₂CH₂—,—CH₂CH₂CH(CH₃)—, —CH₂CH₂CH(OH)—, —CH₂CH(OH)CH₂—O—, —CH₂CH₂CH₂O—,-cyclohexyl-, -pyrrolidinyl-CH₂—, or —CH₂-cyclopropyl-.
 9. A compound ofclaim 7, or salt thereof, wherein L is C(O)NH; and R² is phenylsubstituted with 0-3 R^(2a).
 10. A compound of claim 1, or salt thereof,wherein the compound is selected from:N-methyl-6-[3-({2-(trifluoromethoxy)phenyl]methyl}carbamoyl)piperidin-1-yl-1H-indazole-3-carboxamide;6-(3-{[(2-methoxyphenyl)methyl]carbamoyl}-4-methylpiperazin-1-yl)-N-methyl-1H-indazole-3-carboxamide;6-(2-{[3-(3,4-difluorophenyl)-3-hydroxypropyl]carbamoyl}morpholin-4-yl)-N-methyl-1H-indazole-3-carboxamide;N-methyl-6-{3-[(3-phenylbutyl)carbamoyl]piperazin-1-yl}-1H-indazole-3-carboxamide;N-methyl-6-{1-[(3-phenylbutyl)carbamoyl]piperidin-3-yl}-1H-indazole-3-carboxamide;6-{3-[(2-hydroxy-3-phenoxypropyl)carbamoyl]piperidin-1-yl}-N-methyl-1H-indazole-3-carboxamide;N-methyl-6-(3-1{[(2-phenoxyphenyl)methyl]carbamoyl}piperidin-1-yl)-1H-indazole-3-carboxamide;6-(3-{[3-(cyclohexyloxy)propyl]carbamoyl}piperidin-1-yl)-N-methyl-1H-indazole-3-carboxamide;6-{3-[(3-hydroxy-3-phenylpropyl)carbamoyl]piperidin-1-yl}-N-methyl-1H-indazole-3-carboxamide;6-{3-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]piperidin-1-yl}-N-methyl-1H-indazole-3-carboxamide;6-[3-({[2-(cyclopropylmethoxy)phenyl]methyl}carbamoyl)piperidin-1-yl]-N-methyl-1H-indazole-3-carboxamide;6-(3-{[3-(4-fluorophenoxy)propyl]carbamoyl}piperidin-1-yl)-N-methyl-1H-indazole-3-carboxamide;6-(3-{[3-(3,4-difluorophenyl)-3-hydroxypropyl]carbamoyl}piperidin-1-yl)-N-methyl-1H-indazole-3-carboxamide;N-methyl-6-{3-[(3-phenylcyclohexyl)carbamoyl]piperidin-1-yl}-1H-indazole-3-carboxamide;N-methyl-6-{3-[(3-phenylbutyl)carbamoyl]piperidin-1-yl}-1H-indazole-3-carboxamide;66-{3-[(3-hydroxy-3-phenylpropyl)carbamoyl]-4-methylpiperazin-1-yl}-N-methyl-1H-indazole-3-carboxamide;6-(3-{[3-(4-fluorophenyl)butyl]carbamoyl}-4-methylpiperazin-1-yl)-N-methyl-1H-indazole-3-carboxamide;N-methyl-6-{4-methyl-3-[(3-phenylbutyl)carbamoyl]piperazin-1-yl}-1H-indazole-3-carboxamide;6-{2-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]morpholin-4-yl}-N-methyl-1H-indazole-3-carboxamide;N-methyl-6-{2-[(3-phenylbutyl)carbamoyl]morpholin-4-yl}-1H-indazole-3-carboxamide;6-[2-({[2-(3-fluorophenyl)cyclopropyl]methyl}carbamoyl)morpholin-4-yl]-N-methyl-1H-indazole-3-carboxamide;6-(2-{[3-(4-fluorophenyl)butyl]carbamoyl}morpholin-4-yl)-N-methyl-1H-indazole-3-carboxamide;6-(2-{[3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}morpholin-4-yl)-N-methyl-1H-indazole-3-carboxamide;andN-methyl-6-{2-[(3-phenylcyclohexyl)carbamoyl]morpholin-4-yl}-1H-indazole-3-carboxamide.11. A pharmaceutical composition comprising one or more compounds ofclaim 1, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 12. A method of inhibiting caseinkinase RIPK1 activity in a patient, comprising administering to thepatient in need thereof, a therapeutically effective amount of one ormore compounds according to claim
 1. 13. A method for treating a diseasecomprising the administration to a subject in need thereof atherapeutically effective amount of at least one of claim 12, whereinthe disease is selected from inflammatory bowel disease, ulcerativecolitis, Crohn's disease, psoriasis, rheumatoid arthritis (RA), andheart failure.